The intestinal epithelium not only acts as a physical barrier to commensal bacteria and foreign antigens but is also actively involved in antigen processing and immune cell regulation. The ...inflammatory bowel diseases (IBDs) are characterized by inflammation at this mucosal surface with well‐recognized defects in barrier and secretory function. In addition to this, defects in intraepithelial lymphocytes, chemokine receptors, and pattern recognition receptors promote an abnormal immune response, with increased differentiation of proinflammatory cells and a dysregulated relationship with professional antigen‐presenting cells. This review focuses on recent developments in the structure of the epithelium, including a detailed account of the apical junctional complex in addition to the role of the enterocyte in antigen recognition, uptake, processing, and presentation. Recently described cytokines such as interleukin‐22 and interleukin‐31 are highlighted as is the dysregulation of chemokines and secretory IgA in IBD. Finally, the effect of the intestinal epithelial cell on T effector cell proliferation and differentiation are examined in the context of IBD with particular focus on T regulatory cells and the two‐way interaction between the intestinal epithelial cell and certain immune cell populations. (Inflamm Bowel Dis 2011;)
As a shelf-dominated basin, the Arctic Ocean and its biogeochemistry are
heavily influenced by continental and riverine sources. Radium isotopes
(226Ra, 228Ra, 224Ra, and 223Ra), are transferred from ...the
sediments to seawater, making them ideal tracers of sediment–water exchange
processes and ocean mixing. As the two long-lived isotopes of the radium
quartet, 226Ra and 228Ra (226Ra with a t1∕2 of 1600 years and 228Ra with a t1∕2 of 5.8 years) can provide insight into the water mass
compositions, distribution patterns, as well as mixing processes and their
associated timescales throughout the Canadian Arctic Archipelago (CAA). The
wide range of 226Ra and 228Ra activities, as well as of the
228Ra∕226Ra, measured in water samples collected during the
2015 GEOTRACES cruise, complemented by additional chemical tracers –
dissolved inorganic carbon (DIC), total alkalinity (AT), barium (Ba), and
the stable oxygen isotope composition of water (δ18O) –
highlight the dominant biogeochemical, hydrographic, and bathymetric features
of the CAA. Bathymetric features, such as the continental shelf and shallow
coastal sills, are critical in modulating circulation patterns within the
CAA, including the bulk flow of Pacific waters and the inhibited eastward
flow of denser Atlantic waters through the CAA. Using a principal component
analysis, we unravel the dominant mechanisms and apparent water mass
end-members that shape the tracer distributions. We identify two distinct
water masses located above and below the upper halocline layer throughout
the CAA and distinctly differentiate surface waters in the eastern
and western CAA. Furthermore, we highlight water exchange across
80∘ W, inferring a draw of Atlantic water (originating from Baffin
Bay) into the CAA. This underscores the presence of an Atlantic water “U-turn”
located at Barrow Strait, where the same water mass is seen along the
northernmost edge at 80∘ W as well as along the southeasternmost
confines of Lancaster Sound. Overall, this study provides a stepping stone
for future research initiatives within the Canadian Arctic Archipelago,
revealing how quantifying disparities in the distributions of radioactive
tracers can provide valuable information on water mass distributions, flow
patterns, and mixing within vulnerable areas such as the CAA.
To what extent are the ideas and practice of community development across Europe similar? Community Development and Civil Society explores this question with special reference to the UK and Hungary ...and shows how community development connects powerfully with civil society, a concept that today has global significance.
Paul Henderson and Ilona Vercseg argue that community development is both a profession and a social movement and is relevant to a wide range of issues.They interweave case studies with discussion of principles and theory.The book's critical and accessible approach will appeal especially to students and practitioners.
Background
Many patients with advanced heart failure (HF) are administered chronic intravenous inotropic support (CIIS) as bridge to surgical therapy; some ultimately never receive surgery. We aimed ...to describe reasons patients “crossover” from CIIS as bridge therapy to palliative therapy, and compare end-of-life outcomes to patients initiated on CIIS as palliative therapy.
Methods
Single-institution, retrospective cohort study of patients on CIIS as bridge or palliative therapy between 2010 and 2016; data obtained through review of health records and multi-disciplinary selection meeting minutes, was analyzed using descriptive and inferential statistics.
Results
Of 246 patients discharged on CIIS as bridge therapy, 37 (16%) (male
n
= 28, 76%; African American
n
= 22, 60%) ultimately never received surgery. 67 matched patients on CIIS as palliative therapy were included for analysis (male
n
= 47, 70%; African American
n
= 47, 70%). The most common reasons for “crossover” from CIIS as bridge therapy to palliative therapy were frailty (
n
= 10, 27%), cardiac arrest (
n
= 5, 13.5%), and progressive non-cardiac illnesses (
n
= 6, 16.2%). A similar percentage of patients in the bridge (
n
= 28, 76%) and palliative (
n
= 48, 72%) groups died outside the hospital (
P
=0.66); however, fewer bridge patients received hospice care compared to the palliative group (35% vs 69%,
P
< 0.001). Comparing patients who died in the hospital, bridge patients (
n
= 9; 100%) were more likely to die in the intensive care unit than palliative patients (
n
= 8; 42%) (
P
< 0.001).
Conclusion
Patients on CIIS as bridge therapy who do not ultimately receive surgical therapy “crossover” to palliative intention due to frailty, or development of or identification of serious illnesses. Nevertheless, these “bridge to nowhere” patients are less likely to receive palliative care or hospice and more likely to die in the intensive care unit than patients on CIIS as palliative therapy.
As a shelf-dominated basin, the Arctic Ocean and its biogeochemistry are heavily influenced by continental and riverine sources. Radium isotopes (226Ra, 228Ra, 224Ra, and 223Ra), are transferred from ...the sediments to seawater, making them ideal tracers of sediment–water exchange processes and ocean mixing. As the two long-lived isotopes of the radium quartet, 226Ra and 228Ra (226Ra with a t1/2 of 1600 years and 228Ra with a t1/2 of 5.8 years) can provide insight into the water mass compositions, distribution patterns, as well as mixing processes and their associated timescales throughout the Canadian Arctic Archipelago (CAA). The wide range of 226Ra and 228Ra activities, as well as of the228Ra/226Ra, measured in water samples collected during the 2015 GEOTRACES cruise, complemented by additional chemical tracers – dissolved inorganic carbon (DIC), total alkalinity (AT), barium (Ba), and the stable oxygen isotope composition of water (δ18O) – highlight the dominant biogeochemical, hydrographic, and bathymetric features of the CAA. Bathymetric features, such as the continental shelf and shallow coastal sills, are critical in modulating circulation patterns within the CAA, including the bulk flow of Pacific waters and the inhibited eastward flow of denser Atlantic waters through the CAA. Using a principal component analysis, we unravel the dominant mechanisms and apparent water mass end-members that shape the tracer distributions. We identify two distinct water masses located above and below the upper halocline layer throughout the CAA and distinctly differentiate surface waters in the eastern and western CAA. Furthermore, we highlight water exchange across 80∘ W, inferring a draw of Atlantic water (originating from Baffin Bay) into the CAA. This underscores the presence of an Atlantic water “U-turn” located at Barrow Strait, where the same water mass is seen along the northernmost edge at 80∘ W as well as along the southeasternmost confines of Lancaster Sound. Overall, this study provides a stepping stone for future research initiatives within the Canadian Arctic Archipelago, revealing how quantifying disparities in the distributions of radioactive tracers can provide valuable information on water mass distributions, flow patterns, and mixing within vulnerable areas such as the CAA.
An anthraquinone-linked duplex DNA oligomer containing 60 base pairs was synthesized by PCR. The strand complementary to the quinone-containing strand has four isolated GG steps, which serve as traps ...for a migrating radical cation. Irradiation of the quinone leads to electron transfer from the DNA to the quinone forming the anthraquinone radical anion and a base radical cation. The radical cation migrates through the DNA, causing reaction at GG steps revealed as strand breaks. The efficiency of strand cleavage falls off exponentially with distance from the quinone (slope = -0.02 angstrom -1). This finding necessitates reinterpretation of mechanisms proposed for radical cation migration in DNA. We propose that radical cations form self-trapped polarons that migrate by thermally activated hopping.
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Cisplatin-based therapy is highly toxic, but moderately effective in most cancers. Concurrent inhibition of cyclooxygenase-2 (COX-2) and soluble epoxide hydrolase (sEH) results in antitumor activity ...and has organ-protective effects. The goal of this study was to determine the antitumor activity of PTUPB, an orally bioavailable COX-2/sEH dual inhibitor, in combination with cisplatin and gemcitabine (GC) therapy. NSG mice bearing bladder cancer patient-derived xenografts were treated with vehicle, PTUPB, cisplatin, GC, or combinations thereof. Mouse experiments were performed with two different PDX models. PTUPB potentiated cisplatin and GC therapy, resulting in significantly reduced tumor growth and prolonged survival. PTUPB plus cisplatin was no more toxic than cisplatin single-agent treatment as assessed by body weight, histochemical staining of major organs, blood counts, and chemistry. The combination of PTUPB and cisplatin increased apoptosis and decreased phosphorylation in the MAPK/ERK and PI3K/AKT/mTOR pathways compared with controls. PTUPB treatment did not alter platinum-DNA adduct levels, which is the most critical step in platinum-induced cell death. The
study using the combination index method showed modest synergy between PTUPB and platinum agents only in 5637 cell line among several cell lines examined. However, PTUPB is very active
by inhibiting angiogenesis. In conclusion, PTUPB potentiated the antitumor activity of cisplatin-based treatment without increasing toxicity
and has potential for further development as a combination chemotherapy partner.
.
A multifunctional telodendrimer-based micelle system was characterized for delivery of imaging and chemotherapy agents to mouse tumor xenografts. Previous optical imaging studies demonstrated ...qualitatively that these classes of nanoparticles, called nanomicelles, preferentially accumulate at tumor sites in mice. The research reported herein describes the detailed quantitative imaging and biodistribution profiling of nanomicelles loaded with a cargo of paclitaxel.
The telodendrimer was covalently labeled with ¹²⁵I and the nanomicelles were loaded with ¹⁴C-paclitaxel, which allowed measurement of pharmacokinetics and biodistribution in the mice using microSPECT/CT imaging and liquid scintillation counting, respectively.
The radio imaging data showed preferential accumulation of nanomicelles at the tumor site along with a slower clearance rate than paclitaxel formulated in Cremophor EL (Taxol®). Liquid scintillation counting confirmed that ¹⁴C-labeled paclitaxel sequestered in nanomicelles had increased uptake by tumor tissue and slower pharmacokinetics than Taxol.
Overall, the results indicate that nanomicelle-formulated paclitaxel is a potentially superior formulation compared with Taxol in terms of water solubility, pharmacokinetics, and tumor accumulation, and may be clinically useful for both tumor imaging and improved chemotherapy applications.
Platinum drugs, including carboplatin and oxaliplatin, are commonly used chemotherapy drugs that kill cancer cells by forming toxic drug-DNA adducts. These drugs have a proven, but modest, efficacy ...against several aggressive subtypes of breast cancer but also cause several side effects that can lead to the cessation of treatment. There is a clinical need to identify patients who will respond to platinum drugs in order to better inform clinical decision making. Diagnostic microdosing involves dosing patients or patient samples with subtherapeutic doses of radiolabeled platinum followed by measurement of platinum-DNA adducts in blood or tumor tissue and may be used to predict patient response. We exposed a panel of six breast cancer cell lines to 14C-labeled carboplatin or oxaliplatin at therapeutic and microdose (1% therapeutic dose) concentrations for a range of exposure lengths and isolated DNA from the cells. The DNA was converted to graphite, and measurement of radiocarbon due to platinum-DNA adduction was quantified via accelerator mass spectrometry (AMS). We observed a linear correlation in adduct levels between the microdose and therapeutic dose, and the level of platinum-DNA adducts corresponded to cell line drug sensitivity for both carboplatin and oxaliplatin. These results showed a clear separation in adduct levels between the sensitive and resistant groups of cell lines that could not be fully explained or predicted by changes in DNA repair rates or mutations in DNA repair genes. Further, we were able to quantitate oxaliplatin-DNA adducts in the blood and tumor tissue of a metastatic breast cancer patient. Together, these data support the use of diagnostic microdosing for predicting patient sensitivity to platinum. Future studies will be aimed at replicating this data in a clinical feasibility trial.
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Acute myeloid leukemia (AML) is a rare yet deadly cancer of the blood and bone marrow. Presently, induction chemotherapy with the DNA damaging drugs cytarabine (ARA-C) and idarubicin (IDA), known as ...7 + 3, is the standard of care for most AML patients. However, 7 + 3 is a relatively ineffective therapy, particularly in older patients, and has serious therapy-related toxicities. Therefore, a diagnostic test to predict which patients will respond to 7 + 3 is a critical unmet medical need. We hypothesize that a threshold level of therapy-induced 7 + 3 drug-DNA adducts determines cytotoxicity and clinical response. We further hypothesize that in vitro exposure of AML cells to nontoxic diagnostic microdoses enables prediction of the ability of AML cells to achieve that threshold during treatment. Our test involves dosing cells with very low levels of 14C-labeled drug followed by DNA isolation and quantification of drug-DNA adducts via accelerator mass spectrometry. Here, we have shown proof of principle by correlating ARA-C- and DOX-DNA adduct levels with cellular IC50 values of paired sensitive and resistant cancer cell lines and AML cell lines. Moreover, we have completed a pilot retrospective trial of diagnostic microdosing for 10 viably cryopreserved primary AML samples and observed higher ARA-C- and DOX-DNA adducts in the 7 + 3 responders than nonresponders. These initial results suggest that diagnostic microdosing may be a feasible and useful test for predicting patient response to 7 + 3 induction chemotherapy, leading to improved outcomes for AML patients and reduced treatment-related morbidity and mortality.
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